Synthesis of nicotine derivatives from nicotine

ABSTRACT

Methods of synthesizing nicotine analogs and derivatives are described. In some embodiments the methods utilize an alkyl or aryl silyl-substituted nicotine analog intermediate. Intermediates useful for the synthesis of nicotine and nicotine analogs are also described.

RELATED APPLICATIONS

This application is a divisional of application Ser. No. 11/536,180,filed Sep. 28, 2006, now U.S. Pat. No. 7,361,768 now allowed, which is adivisional of application Ser. No. 11/254,895, filed Oct. 20, 2005, nowU.S. Pat. No. 7,132,545, which is a divisional of application Ser. No.10/925,516, filed Aug. 25, 2004, now U.S. Pat. No. 6,995,265, whichclaims the benefit of U.S. provisional application Ser. No. 60/497,826,filed Aug. 26, 2003, the disclosure of each of which is incorporated byreference herein in its entirety.

FIELD OF THE INVENTION

The present invention concerns methods and intermediates useful for thesynthesis of compounds active for modulating nicotinic acetylcholinereceptors.

BACKGROUND OF THE INVENTION

Acetylcholine receptors are involved in the modulation of a variety ofphysiological and behavioral functions, including neuroendocrinefunction, respiration, mood, motor control and function, focus andattention, concentration, memory and cognition, and substance abuse.Ligands for acetylcholine receptors have been demonstrated to haveeffects on attention, cognition, appetite, substance abuse, memory,extrapyramidal function, cardiovascular function, pain andgastrointestinal motility and function. The distribution ofacetylcholine receptors that bind nicotine, i.e., nicotinicacetylcholine receptors, is widespread in the brain. In the periphery,acetylcholine receptors are found in muscle, autonomic ganglia, thegastrointestinal tract and the cardiovascular system (see, e.g., U.S.Pat. No. 5,594,011).

Acetylcholine receptors have been shown to be decreased, among otherthings, in the brains of patients suffering from Alzheimer's disease,and Parkinson's disease, as well as diseases associated with dementia,motor dysfunction and cognitive impairment. Such correlations betweenacetylcholine receptors and nervous system disorders suggest thatcompounds that modulate acetylcholine receptors will have beneficialtherapeutic effects for many human nervous system disorders. U.S. Pat.No. 5,594,011 to McDonald et al., assigned to SIBIA Neuroscience,describes compounds such as SIB-1508Y that modulate nicotinicacetylcholine receptors. Such compounds are useful for, among otherthings, the treatment of Parkinson's disease. See also U.S. Pat. No.5,723,477 to McDonald et al. Unfortunately, nicotine analogs aredifficult compounds to synthesize, and there is a continuing need fornew methods of making the same, as well as intermediates useful for thesynthesis of nicotine analogs.

SUMMARY OF THE INVENTION

A first aspect of the present invention is a method of making a compoundof Formula i:

wherein:

R², R⁵, and R⁶ are each independently selected from the group consistingof H, alkyl, aryl, alkenyl, alkynyl, alkoxy, and halo, preferably H oralkyl (e.g. methyl);

R⁷ is selected from the group consisting of consisting of H and alkyl(e.g., methyl); and

R²⁰, R²¹ and R²² are each independently selected from the groupconsisting of alkyl and aryl, preferably alkyl such as methyl. Themethod comprises:

reacting a compound of the formula:

with lithium and a compound of the formula XSiR²⁰R²¹R²², where X ishalo, in a polar aprotic solvent to produce the compound of Formula i.

A second aspect of the present invention is a method of making acompound of Formula ii:

wherein R², R⁵, and R⁶ are as given above, R⁷ is as given above, andR²⁰, R²¹ and R²² are as given above. The method comprises oxidizing acompound of Formula i as given above to produce the compound of Formulaii.

A third aspect of the present invention is a method of making a compoundof Formula iii:

wherein R², R⁵, and R⁶ are as given above, R⁷ is as given above, R¹² andR¹³ are each independently selected from the group consisting of H,alkyl and aryl, preferably H or alkyl (e.g., methyl), and R²⁰, R²¹ andR²² are as given above. The method comprises reacting a compound ofFormula i as given above with a compound of the formula:

where X is halo such as chloro in a polar aprotic solvent to produce thecompound of Formula iii.

A fourth aspect of the present invention is a method of making acompound of Formula iv:

wherein R² and R⁶ are as given above, R^(5a) is aryl, such as phenyl;and R⁷ is as given above. The method comprises reacting a compound offormula i as given above, wherein R⁵ is H, and R²⁰, R²¹ and R²² are asgiven above, with a compound of the formula:

in a polar organic solvent containing fluoride to produce the compoundof Formula iv.

A further aspect of the present invention is a method of making acompound of Formula VI:

wherein R² and R⁶ are each independently selected from the groupconsisting of H, alkyl, aryl, alkenyl, alkynyl, alkoxy, and halo(preferably H or alkyl such as methyl), and R⁷ is selected from thegroup consisting of consisting of H and alkyl (preferably methyl). Themethod comprises reacting a compound of Formula V:

with a compound of formula:

where R¹⁴ is alkyl (such as methyl) to produce the compound of FormulaVI:

A further aspect of the present invention is a method of making acompound of Formula V as given above. The method comprises reacting acompound of Formula IV:

where R², R⁶ and R⁷ are as given above with sulfur to produce thecompound of Formula V.

A further aspect of the present invention is a method of making acompound of Formula IV as given above. The method comprises reacting acompound of Formula III:

wherein R², R⁶ and R⁷ are as given above and R¹¹ is alkyl or aryl,preferably alkyl, with a base to produce the compound of Formula IV.

A further aspect of the present invention is a method of making acompound of Formula III as given above. The method comprises reacting acompound of Formula II:

wherein R², R⁶, R⁷, and R¹¹ are as given above, with a compound of theformula POX₃, where X is halo, and a formamide to produce the compoundof Formula III.

A further aspect of the present invention is a method of producing acompound of Formula II as given above. The method comprises reacting acompound of Formula I:

wherein R², R⁶, R⁷, R²⁰, R²¹ and R²² are as given above (note compoundsof Formulas i and Formulas I are the same herein) with a compound of theformula:

where R¹¹ is as given above to produce the compound of Formula II.

A further aspect of the present invention is compounds of Formulas i,ii, iii and iv above, and compounds of Formulas I, II, III, IV and Vabove, which compounds are useful, among other things, as compoundshaving nicotinic acetylcholine receptor modulating activity, and asintermediates for making compounds having nicotinic acetylcholinereceptor modulating activity, all as described in greater detail below.

The foregoing and other objects and aspects of the present invention areexplained in greater detail below.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

“Alkyl” as used herein refers to straight or branched chain alkyl groupshaving in the range of about 1 up to 12 carbon atoms. “Lower alkyl”refers to straight or branched chain alkyl radicals having in the rangeof about 1 up to 4 carbon atoms. Alkyl and loweralkyl may be substitutedor unsubstituted unless specified otherwise herein; “substituted alkyl”refers to alkyl, cycloalkyl or lower alkyl groups further bearing one ormore substituents such as hydroxy, alkoxy (of a lower alkyl group),aryl, mercapto (of a lower alkyl group), halogen, trifluoromethyl,cyano, nitro, amino, carboxyl, carbamate, sulfonyl, sulfonamide, and thelike. Representative examples of alkyl include, but are not limited to,methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl,n-decyl, cyclohexyl, and the like.

“Alkoxy” as used herein refers to a compound of the formula RO—, where Ris alkyl or loweralkyl (which may be substituted or unsubstituted unlessspecified otherwise) as given above.

“Alkenyl” refers to straight or branched chain hydrocarbyl groups suchas alkyl or loweralkyl groups as described above (and which may besubstituted or unsubstituted unless specified otherwise) and having atleast one carbon-carbon double bond.

“Alkynyl” refers to straight or branched chain hydrocarbyl groups suchas alkyl or loweralkyl groups as described above (and which may besubstituted or unsubstituted unless specified otherwise) and having atleast one carbon-carbon triple bond.

“Aryl,” as used herein, refers to a monocyclic carbocyclic ring systemor a bicyclic carbocyclic fused ring system having one or more aromaticrings. Examples of aryl include but are not limited to azulenyl,indanyl, indenyl, naphthyl, phenyl, tetrahydronaphthyl, and the like.The aryl groups may be substituted or unsubstituted unless specifiedotherwise and when substituted can for example be substituted with 1, 2,3, 4, or 5 substituents independently selected from alkyl, alkenyl,alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkylcarbonyl,alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl,aryl, aryloxy, azido, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano,formyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, mercapto,nitro, sulfamyl, sulfo, sulfonate, —NR′R″ (wherein R′ and R″ areindependently selected from hydrogen, alkyl, alkylcarbonyl, aryl,arylalkyl and formyl), and —C(O)NR′R″ (wherein R′ and R″ areindependently selected from hydrogen, alkyl, alkylcarbonyl, aryl,arylalkyl, and formyl).

“Halo” refers to fluoro, chloro, bromo or iodos.

The disclosures of all United States patent references cited herein areto be incorporated herein by reference in their entirety.

In a first aspect, the present invention provides a set of reactions forthe synthesis of derivatives from nicotine and nicotine analogs. Thisset of reactions is referred to with reference to compounds of Formulasi-iv herein. Thus in one respect the present invention provides a methodof making a compound of Formula i:

wherein R², R⁵, and R⁶ are each independently selected from the groupconsisting of H, alkyl, aryl, alkenyl, alkynyl, alkoxy, and halo(preferably H and alkyl, most preferably H), R⁷ is selected from thegroup consisting of consisting of H and alkyl (preferably alkyl, mostpreferably methyl), and R²⁰, R²¹, and R²² are alkyl or aryl (preferablyalkyl, most preferably methyl). Compounds that may be used as startingmaterials for the reactions described herein (including the preparationof compounds of Formula i) include both nicotine and nicotine analogsand derivatives, particularly analogs substituted at the 2 and 6position, including but not limited to those described in U.S. Pat. Nos.5,594,011 and 5,723,477. The method comprises reacting a precursornicotine or nicotine analog such as compounds of the formula:

(which precursor nicotine or nicotine analog may be produced inaccordance with known techniques as noted above) with lithium (e.g.,lithium powder) and a compound of the formula XSiR²⁰R²¹R²² where X ishalo preferably chloro (and the compound is preferablytrialkylchlorosilane, most preferably trimethylchlorosilane) in a polaraprotic solvent (such as tetrahydrofuran) to produce the compound ofFormula i. The method may be carried out for any suitable time andtemperature, such as −20° C. to 25° C. or more, and is preferablycarried out at a temperature of about 0° C.

A further aspect of the present invention is a method of making acompound of Formula ii:

wherein R², R⁵, and R⁶, R⁷, R²⁰, R²¹ and R²² are as given above. Themethod comprises oxidizing a compound of Formula i as described above toproduce the compound of Formula ii. The method may be carried out withany suitable oxidizing agent, preferably air. Compounds of Formula iiare useful as insecticides for insects such as mosquitoes and are usefulas intermediates for making nicotine and nicotine analogs.

The present invention further provides a method of making a compound ofFormula iii:

wherein R², R⁵, R⁶, R⁷, R²⁰, R²¹ and R²² are as described above, and R¹²and R¹³ are each independently selected from the group consisting of H,alkyl, and aryl (preferably alkyl, most preferably methyl). In general,the method comprises reacting a compound of Formula i as described abovewith a compound of the formula

where X is halo, preferably chloro. The reaction may be carried out in apolar aprotic solvent, preferably methylene chloride, at any suitabletemperature, typically from 0° C. to 100° C., and preferably at roomtemperature.

The present invention further provides a method of making a compound ofFormula iv:

wherein R^(5a) is substituted or unsubstituted aryl, and R², R⁶ and R⁷are as given above. The method comprises reacting a compound of formulai, wherein R⁵ is H, with a compound of the formula:

in a polar organic solvent such as tetrahydrofuran containing fluoride(preferably by addition of a fluoride source such as TBAF) to producesaid compound of Formula iv.

Reactions for the synthesis of compounds such as SIB-1508Y. In anotherrespect, the present invention provides methods for the synthesis ofcompounds having acetylcholine receptor modulating activity includingpharmaceutical compounds or insecticides from nicotine and nicotineanalogs. These methods are referred to with respect to compounds ofFormulas I-VI herein. In one aspect, such methods involve methods ofmaking compounds of Formula II:

wherein R¹¹ is alkyl or aryl (preferably alkyl, most preferably methyl),and R², R⁶, and R⁷ are as given above. Such compounds may be made byreacting a compound of Formula i above (in this section referred to asFormula I):

with a compound of the formula:

(wherein R¹¹ is as given above) in a polar aprotic solvent such astetrahydrofuran containing fluoride (e.g., by addition oftetrabutylammonium fluoride or other appropriate fluoride source) toproduce the compound of Formula II. The reaction may be carried out atany suitable temperature, for example from 10 to 50 or 75° C.,preferably room temperature.

A further aspect of the invention is a method of making compounds ofFormula III:

wherein R², R⁶, R⁷ and R¹¹ is as given above. Such compounds may beproduced by reacting a compound of Formula II as described above withPOX₃ where X is halo, preferably chloro, and a formamide (preferably adialkyl formamide and most preferably dimethylformamide) in a polaraprotic solvent such as methylene chloride, chloroform, carbontetrachloride or the like to produce said compound of Formula III. Thereaction may be carried out at any suitable temperature, typicallybetween room temperature and 100° C.

A further aspect of the present invention is a method of makingcompounds of Formula IV:

wherein R², R⁶ and R⁷ are as given above. Such methods generally involvereacting a compound of Formula III as described above with a base,preferably a mild base such as triethylamine, an alkoxide or methoxidesuch as sodium, lithium or potassium alkoxide or methoxide, in a polarorganic solvent (e.g., methanol, ethanol, propanol) to produce thecompound of Formula IV. The reaction can be carried out under anysuitable conditions, typically from 0 to 100° C., preferably at roomtemperature.

The present invention provides methods of making compounds of Formula V:

(wherein R², R⁶ and R⁷ are as given above) by reacting a compound ofFormula IV as described above with sulfur (e.g., elemental sulfur) in apolar or nonpolar organic solvent (e.g., toluene, benzene, highermolecular weight non-polar solvents, alcohols) to produce the compoundof Formula V. Such reactions may be carried out under any suitableconditions, preferably by reflux, for any suitable time (e.g., 1-24hours).

Finally, the present invention provides methods of making compounds ofFormula VI:

wherein R², R⁶ and R⁷ are as given above. The methods comprise reactinga compound of Formula V as described above with a compound of formula:

wherein R¹⁴ is alkyl, preferably methyl, in the presence of a strongbase (i.e., potassium tert-butoxide) in a polar aprotic solvent such astetrahydrofuran to produce the compound of Formula VI.

Compounds of Formula VI are useful in the manners described in U.S. Pat.No. 5,594,011 to McDonald et al. and U.S. Pat. No. 5,723,477 to McDonaldet al., and compounds of Formulas I-V are useful as intermediates formaking the same.

In summary, methods and intermediates of the present invention areuseful for producing pharmacologically and pharmaceutically activecompounds, including compounds useful for the treatment of neurologicaldisorders such as Parkinson's disease, Alzheimer's disease, motordysfunction and cognitive impairment in human and animal subjects, aswell as compounds for use as an alternative to nicotine as an aid tosmoking cessation programs, as insecticides, etc.

The present invention is explained in greater detail in the followingnon-limiting Examples.

EXAMPLES 1-3 Preparation of Enantiopure Nicotine Derivatives i-iv

EXAMPLES 1-2 Preparation of(S)-3-(1-Methylpyrrolidin-2-yl)-1,4-bis-trimethylsilanyl-1,4-dihydropyridine(i) and (S)-3-(1-Methylpyrrolidin-2-yl)-4-trimethylsilanylpyridine (ii)

To a suspension of lithium powder (0.42 g, 60 mmol) in freshly distilledTHF (20 mmol) cooled at −10° C. was added freshly distilledtrimethylchlorosilane (7.6 mL, 60 mmol). A solution of (S)-nicotine (3.2mL, 20 mmol) in THF (20 mL) was injected dropwise over 20 min. Thereaction mixture was stirred at 0° C. for 1 h. The precipitate formedwas decanted over 2 h and the liquid portion was cannulated into a 2neck flask mounted with a distillation apparatus under Ar. After removalof the THF by distillation at atmospheric pressure, the product wasdistilled under vacuum (1.5 mm Hg, bp=130-135° C.) to give 71% (4.36 g)of3-(1-methylpyrrolidin-2-yl)-1,4-bis-trimethylsilanyl-1,4-dihydropyridinei as a yellow oil (95% pure by NMR). ¹H NMR (400 MHz, CDCl₃): δ 8.24 (s,1 H), 5.78-5.72 (m, 1 H), 4.37-4.29 (m, 1 H), 3.06-2.93 (m, 1 H),2.4-1.4 (m, 10 H), 0.08 (s, 9 H), −0.05 (s, 9 H). ¹³C NMR (100 MHz,CDCl₃) δ 127.49, 126.41, 121.14, 102.08, 101.00, 66.67, 57.21, 41.05,32.52, 26.41, 21.84, −0.83, −0.90, −2.43, −2.64. HRMS Calcd forC₁₆H₃₂N₂Si₂: 309.2182 [M+H]⁺. Found: 309.2166 [M+H]⁺.

3-(1-Methylpyrrolidin-2-yl)-1,4-bis-trimethylsilanyl-1,4-dihydropyridinei is easily converted to3-(1-methylpyrrolidin-2-yl)-4-trimethylsilanylpyridine ii when incontact with air. Compound II can be purified by RPLC (silica gel, 5%EtOAc/hex) to give a clear oil. IR (thin film, neat, NaCl): 2955, 2768,1338, 1243, 1844 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 8.86 (s, 1 H), 8.42(d, 1 H, J=6.4 Hz), 7.28 (dd, 1 H, J=1.2 and 6.8 Hz), 3.36-3.24 (m, 2H), 2.35-1.60 (m, 8 H), 0.37 (s, 9 H); ¹³C NMR (100 MHz, CDC₃) δ 149.16,147.64, 147.01, 127.88, 68.89, 56.94, 40.45, 36.50, 22.82, 0.51. HRMSCalcd for C₁₃H₂₂N₂Si: 235.1631[M+H]⁺. Found: 235.1639 [M+H]⁺. [α]²⁵_(D)−124.1 (CH₂Cl₂, c=4.9).

EXAMPLE 3 Preparation of(S)-3-(1-methylpyrrolidin-2-yl)-4-trimethylsilanyl-4H-pyridine-1-carboxylicacid dimethylamide (iii)

To a stirred solution of3-(1-methylpyrrolidin-2-yl)-1,4-bis-trimethylsilanyl-1,4-dihydropyridinei (0.2 mL, 1.36 mmol) in CH₂Cl₂ (6 mL) under Ar was added dropwisedimethylcarbamyl chloride (0.19 mL, 2.04 mmol). The reaction mixture wasstirred at RT for 1 day. It was then poured into a saturated solution ofNaHCO₃ (3 mL). The aqueous phase was extracted with CH₂Cl₂ (5 times).The combined organic layers were washed with water and brine and driedover MgSO₄. Evaporation of the solvent under reduced pressure afforded0.49 g of crude material that was purified by RPLC (silica gel, 5%EtOAc/hex) to give 59% (0.2506 g) of3-(1-methylpyrrolidin-2-yl)-4-trimethylsilanyl-4H-pyridine-1-carboxylicacid dimethylamide iii as a clear oil. IR (thin film, neat, NaCl): 3363,2924, 2348, 1657, 1449, 1377 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 6.65 (d,1H, J=6.9 Hz), 6.35 (s 1H), 4.83-4.78 (m, 1 H), 3.14-3.09 (m, 1 H), 2.88(s, 6 H), 2.80-1.25 (m, 13 H), 0.085 (s, 6 H); ¹³C NMR (100 MHz, CDCl₃):δ 149.29, 147.15, 128.04, 124.49, 120.09, 106.29, 68.23, 57.35, 41.47,38.53, 33.04, 30.34, 29.91, 22.37, 0.63, −2.00. HRMS Calcd forC₁₆H₂₉N₃OSi: 308.2157 [M+H]⁺. Found: 308.2157 [M+H]⁺. [α]²⁵ _(D) −15.17(CH₂Cl₂, c=0.145).

EXAMPLE 4 Preparation of(S)-3-benzyl-5-(1-methylpyrrolidin-2-yl)-pyridine iv

To a stirred solution of benzaldehyde (0.07 mL, 0.75 mmol) in freshlydistilled THF was added dropwise3-(1-methylpyrrolidin-2-yl)-1,4-bis-trimethylsilanyl-1,4-dihydropyridinei (0.21 g, 0.68 mmol). A degassed solution of TBAF in THF (1 M) storedover molecular sieves was slowly added to the mixture. The reactionmixture was stirred under Ar at RT for one day. It was then poured intoa saturated aqueous solution of NaHCO₃. The product was extracted withdiethyl ether (2 times). The combined organic layers were washed withbrine and dried over MgSO₄. The solvent was evaporated under reducedpressure and the residue was purified by RPLC (silica gel, 10%MeOH/EtOAc) to give 31% (0.0525 g) of(S)-3-benzyl-5-(1-methylpyrrolidin-2-yl)-pyridine iv as a clear oil. IR(thin film, neat, NaCl): 3236, 2954, 2778, 1666, 1613, 1449, 1037 cm⁻¹.¹H NMR (400 MHz, CDCl₃) δ 8.40-8.34 (m, 2 H), 7.88 (dd, 1 H, J=1.6 and13.2 Hz), 7.37-7.24 (m, 4 H), 5.84 (s, 1 H), 3.13-3.02 (m, 2 H),2.25-1.69 (m, 10 H); ¹³C NMR (75 MHz, CDCl₃) δ 148.43, 147.42, 143.90,140.11, 138.19, 133.30, 133.25, 128.82, 127.95, 126.81, 74.24, 74.03,69.15, 57.04, 40.47, 35.10, 22.51. HRMS Calcd for C₁₇H₂₀N₂: 252.1626[M+H]⁺. Found: 252.1635 [M+H]⁺. [α]²⁵ _(D) −26 (CH₂Cl₂, c=1.51).

EXAMPLES 5-9 Preparation of(S)-(−)-5-ethenyl-3-(1-methyl-2-pyrrolidinyl)pyridine maleate VI(SIB-1508Y)

These examples show the preparation of a compound, SIB-1508, by methodsand intermediates of the present invention. Note that compound I is thesame as compound i in examples 1-4 above, but that compounds II-IVherein are different structures than those assigned compound numbersii-iv in Examples 1-4 above.

EXAMPLE 5 Preparation of(S)-3-(1-Methylpyrrolidin-2-yl)-4H-pyridine-1-carboxylic acid methylester II

To a solution of dimethyl carbonate (0.05 mL, 0.6 mmol) in 2 mL of dryTHF was slowly added3-(1-methylpyrrolidin-2-yl)-1,4-bis-trimethylsilanyl-1,4-dihydropyridineI (0.2 mL, 0.68 mmol). A solution of TBAF in THF (0.06 mL, 0.06 mmol)was then introduced dropwise and the reaction mixture was stirred at RTfor 1 h. The reaction was quenched with a saturated aqueous solution ofNaHCO₃. The aqueous layer was extracted with ether (2 times), and thecombined organic layers were washed with brine and dried over K₂CO₃. Thesolvent was removed under reduced pressure and the crude material waspurified by RPLC (hexanes) to afford 0.1374 g (91%) of3-(1-methylpyrrolidin-2-yl)-4H-pyridine-1-carboxylic acid methyl esterII as a clear oil. IR (thin film, neat, NaCl): 2949, 2826, 2764, 1721,1695, 1437, 1334, 1313, 1194, 983 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ6.68-6.51 (m, 2 H), 4.88-4.77 (m, 1 H), 3.65 (s, 3 H), 2.95-2.91 (m, 1H), 2.64-2.62 (m, 2 H), 2.41-2.33 (m, 1H), 2.05-1.93 (m, 5 H), 1.68-1.53(m, 4 H); ¹³C NMR (CDCl₃, 75 MHz) δ 151.81, 123.15, 122.74, 120.28,119.63, 118.08, 117.71, 106.22, 105.94, 70.37, 56.60, 53.05, 40.16,40.08, 28.76, 28.38, 22.37, 21.56, 21.05. HRMS Calcd for C₁₂H₁₈N₂O₂:223.1447 [M+H]⁺. Found: 223.1434 [M+H]⁺. [α]²⁴ _(D) −65.5 (c=8, CH₂Cl₂).

EXAMPLE 6 Preparation of(S)-3-formyl-5-(1-methylpyrrolidin-2-yl)-4H-pyridine-1-carboxylic acidmethyl ester (III)

To a solution of DMF (0.04 mL, 0.54 mmol) in 4 mL of CH₂Cl₂ cooled at 0°C. was slowly added POCl₃ (0.025 mL, 0.27 mmol). The ice bath wasremoved and the mixture was stirred at RT for 30 min. It was thentransferred via a double tipped needle to a solution of3-(1-methyl-pyrrolidin-2-yl)-4H-pyridine-1-carboxylic acid methyl esterII (0.0404 g, 0.18 mmol) in 4 mL of CH₂Cl₂ cooled at 0° C. The reactionmixture was stirred at RT for 1 day. A solution of NaOAc (0.024 g, 0.29mmol) in 0.5 mL of water was added and the reaction mixture was stirredat RT for 20 min. A saturated aqueous solution of NaHCO₃ was slowlyadded until pH was basic (about 10 mL). The aqueous layer was extractedwith CH₂Cl₂ (4 times), and the combined organic layers were dried overMgSO₄. After evaporation of the solvent under reduced pressure, thecrude material was purified by RPLC (15% EtOAc/hexanes) to afford 0.0241g (54%) of(S)-3-formyl-5-(1-methylpyrrolidin-2-yl)-4H-pyridine-1-carboxylic acidmethyl ester III as white crystals, mp 78-80° C. IR (thin film, neat,NaCl): 2955, 2767, 1731, 1667, 1620, 1437, 1394, 1203, 991 cm⁻¹; ¹H NMR(CDCl₃, 300 MHz) δ 9.45 (s, 1 H), 7.65 (m, 1 H), 6.81 (s, 1 H), 3.91 (s,3 H), 3.12-3.07 (m, 1 H), 2.93 (s, 2 H), 2.59 (m, 1 H), 2.20-2.12 (m, 3H), 1.81-1.62 (m, 5 H); ¹³C NMR (CDCl₃, 75 MHz) δ 191.13, 141.44,122.61, 120.52, 118.42, 69.75, 56.98, 54.47, 40.61, 29.45, 22.91, 19.86.HRMS Calcd for C₁₃H₁₈N₂O₃: 251.1396 [M+H]⁺. Found: 251.1390 [M+H]⁺.[α]²⁵ _(D) −51.7 (c=0.8, CH₂Cl₂).

EXAMPLE 7 Preparation of(S)-5-(1-methylpyrrolidin-2-yl)-1,4-dihydropyridine-3-carbaldehyde (IV)

To a solution of(S)-3-formyl-5-(1-methyl-pyrrolidin-2-yl)-4H-pyridine-1-carboxylic acidmethyl ester III (0.0124 g, 0.05 mmol) in 2 mL of anhydrous MeOH wasslowly added triethylamine (0.02 mL, 0.15 mmol), and the reactionmixture was stirred at RT for 1 day. Evaporation of the solvent affordeda quantitative yield (0.010 g) of(S)-5-(1-methylpyrrolidin-2-yl)-1,4-dihydro-pyridine-3-carbaldehyde IVas a yellow oil. The product was used without further purification. IR(thin film, neat, NaCl): 3416-3244, 2957, 1595, 1509, 1377, 1228 cm⁻¹.¹H NMR (CDCl₃, 300 MHz) δ 9.14 (s, 1 H), 6.85 (d, 1 H, J=6 Hz), 6.48 (s,1 H), 6.00-5.99 (m, 1 H), 3.05-3.00 (m, 3 H), 2.45 (m, 1 H), 2.19-2.11(m, 4 H), 1.83-1.67 (m, 4 H); ¹³C NMR (CDCl₃, 75 MHz) δ 189.59, 146.95,119.91, 119.01, 112.67, 70.03, 57.03, 40.69, 28.96, 22.80, 20.37. HRMSCalcd for C₁₁H₁₆N₂O: 193.1341 [M+H]⁺. Found: 193.1334 [M+H]⁺. [α]²⁸ _(D)−80.7 (c=0.55, CH₂Cl₂).

EXAMPLE 8 Preparation of(S)-5-(1-methylpyrrolidin-2-yl)pyridine-3-carbaldehyde (V)

A solution of(S)-5-(1-methylpyrrolidin-2-yl)-1,4-dihydropyridine-3-carbaldehyde IV(0.011 g, 0.044 mmol) and elemental sulfur (0.0015 g, 0.044 mmol) in 2mL of toluene was refluxed for 1 day. After filtration through a pad ofCelite, and evaporation of the solvent under reduced pressure, the crudematerial was purified by RPLC (silica gel, 5% EtOAc/hexanes then EtOAc)to afford 0.007 g (83%) of5-(1-methylpyrrolidin-2-yl)pyridine-3-carbaldehyde V as a clear oil. IR(thin film, neat, NaCl): 2950, 1586, 1370, 1120 cm⁻¹. ¹H NMR (CDCl₃, 300MHz) δ 10.13-10.12 (m, 1 H), 8.97-8.96 (m, 1 H), 8.79 (s, 1 H), 8.18 (s,1 H), 3.30-3.20 (m, 2 H), 2.38-1.67 (m, 4 H); ¹³C NMR (CDCl₃, 100 MHz) δ191.26, 154.81, 150.91, 135.13, 131.69, 68.53, 57.19, 40.64, 40.64,35.66, 23.02. HRMS Calcd for C₁₁H₁₄N₂O: 191.1184 [M+H]⁺. Found: 191.1182[M+H]⁺. [α]²³ _(D) −92 (c=0.2, CH₂Cl₂).

EXAMPLE 9 Revised Preparation of(S)-3-ethynyl-5-(1-methylpyrrolidin-2-yl)pyridine or SIB-1508Y (VI)

To a solution of tBuOK in THF (0.08 mL, 0.08 mmol) cooled at −78° C. wasadded dropwise a solution of methyl diazomethyl phosphonate in THF (0.1mL, 0.08 mmol). The solution was stirred at −78° C. for 5 min, then asolution of 5-(1-methylpyrrolidin-2-yl)pyridine-3-carbaldehyde (V)(0.0126 g, 0.066 mmol) in THF (1 mL) was added via a double tippedneedle. The reaction mixture was stirred at −78° C. for 16 h thenallowed to warm to RT over 2 h. After evaporation of the solvent underreduced pressure, the crude material was purified by RPLC (silica gel,10% EtOAC/hexanes) to afford 0.0061 g (51%) of3-ethynyl-5-(1-methylpyrrolidin-2-yl)-pyridine (VI) as a clear oil. Thedata were identical to those described in the literature (Bleicher, L.S.; Cosford, N. P. D.; Herbault, A.; McCallum, J. S.; McDonald, I. A. J.Org. Chem. 1998, 63, 1109).

The foregoing is illustrative of the present invention, and is not to beconstrued as limiting thereof. The invention is defined by the followingclaims, with equivalents of the claims to be included therein.

1. A method of making a compound of Formula VI:

wherein: R² and R⁶ are each independently selected from the groupconsisting of H, alkyl, aryl, alkenyl, alkynyl, alkoxy, and halo, and R⁷is selected from the group consisting of consisting of H and alkyl;comprising the steps of reacting a compound of Formula V:

with a compound of formula:

where R¹⁴ is alkyl to produce said compound of Formula VI.
 2. The methodof claim 1, wherein said compound of Formula V is produced by reacting acompound of Formula IV:

with sulfur in a polar or nonpolar organic solvent to produce saidcompound of Formula V.
 3. The method of claim 2, wherein said compoundof Formula IV is produced by reacting a compound of Formula III:

wherein R¹¹ is alkyl or aryl, with a base in a polar organic solvent toproduce said compound of Formula IV.
 4. The method of claim 3, whereinsaid compound of Formula III is produced by reacting a compound ofFormula II:

with POX₃, where X is halo, and a formamide in a polar aprotic solventto produce said compound of Formula III.
 5. The method of claim 4,wherein said compound of Formula II is produced by reacting a compoundof Formula I:

wherein R²⁰, R²¹ and R²² are alkyl or aryl with a compound of theformula:

in a polar aprotic solvent containing fluoride to produce said compoundof Formula II.
 6. The method of claim 1, wherein R² and R⁶ are H, and R⁷is methyl.
 7. The method of claim 1, wherein R¹⁴ is methyl.
 8. Themethod of claim 3, wherein R¹¹ is methyl.
 9. The method of claim 4,wherein X is chloro.
 10. The method of claim 5, wherein R²⁰, R²¹ and R²²are each methyl.